Large granular lymphocyte (LGL) leukemia is a human lymphoproliferative disorder often associated with autoimmune disease, such as rheumatoid arthritis. The etiology of LGL leukemia is not known. Large granular lymphocyte are a morphologically recognizable lymphoid subset comprising 10%-15% of peripheral blood mononuclear cells. LGL can be divided into two major lineages: CD3-negative cells (CD3−) and CD3-positive cells (CD3+). CD3−LGL are natural killer (NK) cells that mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity and do not express the CD3/T-cell receptor (TCR) complex or rearrange TCR genes. CD3+LGL are T-cells that do express CD3/TCR complex and rearrange TCR genes. A syndrome of increased numbers of circulating LGL associated with chronic neutropenia was first recognized as a distinct clinical entity in 1977. LGL proliferations are now known to be clonally derived from either of their counterparts (CD3− or CD3+LGL). Although the etiology of LGL leukemia has not been fully elucidated, some evidence suggests that the initiation event may involve an HTLV-I like retrovirus.
Examination of the peripheral blood is critical for establishing the diagnosis of LGL leukemia. Characteristic features of the disease include larger than normal lymphocytes with abundant pale cytoplasm and prominent azurophilic granules. Patients with clonal CD3+LGL (T-LGL) possess clonally derived lymphocytes with a CD3+, CD16+ and CD57+ phenotype. Autoimmune features are characteristic of this disease, and these patients resemble that of Felty's syndrome and present with the clinical triad of rheumatoid arthritis, neutropenia and splenomegaly. Morbidity and mortality most often results from infections acquired during severe neutropenia. The mechanism underlying the neutropenia is not well understood. Interestingly up to 40% of patients with T-cell LGL have rheumatoid arthritis. Although the cause of T-LGL leukemia and the events initiating the development of rheumatoid arthritis are now known, it has been hypothesized that there may be a common etiology underlying both diseases. Patients with NK-LGL possess clonally expanded LGL with a CD3−, CD4−, CD8−, CD16+ and CD56+ phenotype. In spite of aggressive treatment with multi-agent chemotherapy, 80% of these patients die within two months of diagnosis due to disseminated disease with multi-organ failure.
Cytotoxic T lymphocytes (CTL) are CD8+ T cells activated in response to antigen. Such CTL can be categorized into naïve CD8+ cells, terminally differentiated effector cells which are likely to undergo apoptosis, and a minor proportion of long-term CD8+ memory cells. These memory cells proliferate in the presence of antigen (Butz et al., 1998). Cell-mediated killing by cytotoxic T-lymphocytes is an important event to protect the host against viral infection and tumor cell proliferation (Crabtree et al., 1994; Grakoui et al., 1999). Cytotoxic T cells are loaded with granules containing various effector molecules that are capable of killing target cells. Upon contact with target cells, the cytotoxic cells release cytotoxic molecules vectorially into the target cells and destroy them. Once the antigen is cleared from the system, the majority of the cytotoxic T cells (terminally differentiated cells) die primarily through Fas-mediated apoptosis in order to maintain homeostasis (Nagata et al., 1995; Callan et al., 2000; Zimmerman et al., 1996). In lymphoproliferative disorders such homeostasis is not maintained, resulting in the accumulation of a large number of lymphocytes. This may be due to defective apoptotic pathways in effector CD8+ cells or due to the constant presence of antigen leading to a continuous proliferation of cells.
The T cell form of large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder often associated with autoimmune disease (Loughran, Jr., 1993; Lamy et al., 1999). Several lines of research suggest that leukemic LGL are antigen activated CTL. Leukemic LGL display an activated cytotoxic T-cell phenotype (Loughran, Jr., 1993). Activation of leukemic LGL can be triggered through CD3 and/or CD16 pathways (Hoshino et al., 1991; Loughran et al., 1990). Leukemic LGL constitutively express perforin and Fas ligand which, besides NK cells, are found expressed only in T cells activated for killing (Oshimi et al., 1990; Lamy et al., 1998). A restricted T cells receptor repertoire has been found in some studies of LGL leukemia, suggesting antigen selection (Zambello et al., 1995; Kasten-Sportes et al., 1994).